Download Gender Related Differences in Pharmacokinetics and

Gender-related differences in
pharmacokinetics and
pharmacodynamics
Petra A. Thürmann
Philipp Klee-Institute of Clinical Pharmacology
HELIOS Hospital Wuppertal
Chair of Clinical Pharmacology
University Witten/Herdecke
• absorption,
distribution,
metabolism and
elimination
• effect at the receptor
level, efficacy and
adverse drug reactions
• ... and the enrolment
of women in clinical
trials with new and old
drugs
Blood level
Gender- or sex-specific differences
in pharmacokinetics and -dynamics
Time (min)
Women in clinical trials – an analysis of
studies submitted to the FDA
46
Phase unknown
54
An
Phase II
45
Phase II
48
Phase I
55
52
25
75
Women
Men
0%
20%
40%
60%
80% 100%
Women
s
ral
i
v
ti
Men
Sex unknown
cs
e ti
th
es
a
An
y
l og
o
c
On
S
CN
.
sc
a
v
dio
r
0%
Ca
20% 40% 60% 80% 100%
n=2.581 trials, n=334.551 Patients, excl. Studies with sex-specific drugs
Evelyn B et al, FDA, 24.8.2001
Inclusion of women in clinical trials
published in 2001
% clinical trials with…
90
80
70
m+f
men only
not specified
60
50
40
30
20
10
0
healthy volunteers
N = 239 trials with
n = 15,880 patients/volunteers
patients
Clinical Pharmacology & Therapeutics (IF 5,6)
British Journal of Clinical Pharmacology (IF 1,8)
European Journal of Clinical Pharmacology (IF2,1)
Fleisch, Fleisch & Thürmann, CP&T 2005
Reasons to exclude women
from clinical trials
Ethical reasons
• Potential risk of pregnancy
• Experience with thalidomide and
diethylstilbestrol
Juridical reasons
• Liability
Methodological Reasons
• Inter-individual variability increases
• Interactions with oral contraceptives
Pharmakokinetics:
sex-based differences
Body weight is in average 10 kg lower
in women when compared with men
Women tend to have a higher
percentage of body fat and –
depending on the menstrual cycle –
a variable water content
Women metabolize endogenous sex
hormones to a higher extent than
men  liver function and metabolic
capacity differ
Metabolism at the microsomal
cytochrome P450 system
60
%
50
40
30
20
10
0
CYP3A
CYP3A CYP2D6 CYP2C CYP1A2 CYP2E1
Sex-based differences in the expression of
CYP3A4-mRNA and enzyme activity in
human liver microsomes
CYP3A4 mRNA-expression
CYP3A4 protein content in relation to
verapamil-N-dealkylation
Wolbold R et al, Hepatology 2003
Tirilazad and subarachnoidal haemorrhage
% 100
Women
90
80
70
60
50
40
30
20
10
0
Placebo
Tirilazad 6 mg/kg/d
Men
P < 0,05
P < 0,05
++ = good recovery
(Glasgow Outcome
Scale)
+ = moderate –
severe dysfunction
(Glasgow Outcome
Scale)
++
+
Death
++
+
Death
Kassell NF et al, J Neurosurg 1996
Plasma concentrations of tirilazad mesylate
after 3 mg/kg i.v.
P < 0.05
P < 0.05
9
8
7
6
5
4
3
2
1
0
men < 40
men 40-60
women <40
women 40-60
*P<0.05 m vs. w
Hulst LK et al, Clin Pharmacol Ther 1994
Double-blind, randomized, vehicle-controlled study
of high-dose tirilazad mesylate in women with SAH
• Findings from previous multicenter clinical trials have
suggested that tirilazad mesylate might be effective in
preventing delayed cerebral ischemia following
subarachnoid hemorrhage (SAH). This beneficial effect,
however, was greater in males than females, possibly
because of gender-related pharmacokinetic differences.
• The authors sought to assess the effects of administering
a larger dose of tirilazad in women with SAH.
• CONCLUSIONS: The authors conclude that high-dose
tirilazad mesylate is well tolerated in women with
aneurysmal SAH. Although a significant reduction in the
incidence of symptomatic vasospasm was observed in
the treatment group, the primary end point (mortality rate
at 3 months post-SAH) was not affected by the study
drug.
Lanzino G et al, J Neurosurg 1999
Pharmakokinetics of metoprolol –
a CYP2D6 substrate
Maximum plasma concentration
Area under the
concentration/time curve
900
160
Women
men
800
120
*
100
*
80
60
AUC (ng/ml*h)
140
Women
Men
700
600
500
*
*
400
*
*
300
40
200
20
100
0
0
S-Enant.
R-Enant.
S-Enant.
R-Enant.
*p < 0,05 women versus men
Luizer et al, Clin Pharm Ther 1999
Influence of oral contraceptives (OC)
on the pharmacokinetics of metoprolol
200
5
1600
4
150
1200
3
800
100
2
400
50
0
0
1
11 females without OC
0
12 females with OC
Kendall MJ et al; Br J Clin Pharmacol 1982
Adverse drug reactions with
betablockers resulting in hospitalisation
number
30
CYP2D6-dependent
CYP2D6substrates:
metoprolol,
carvedilol,
nebivolol,
propranolol
25
27
CYP2D6-independ
ent
20
14
15
12
10
12
3
2
5
3
0
2 beta-blockers
bisoprolol
3
sotalol
propranolol
2
carvidolol
metoprolol
0
5
4
other
5
15
7
atenolol
7
7
nebivolol
5
woman
men
CYP2D6independent
betablockers:
sotalol, bisoprolol,
atenolol
Thürmann et al, German Pharmacovigilance Study Group 2006
Population pharmacokinetics
of 5-fluouracil
Gusella et al, BJCP 2002
Women experience greater toxicity with fluorouracilbased chemotherapy for colorectal cancer
% patients
with ADRs 60
severity
50
grade  3 40
*
30
*
20
10
Rs
al
lA
D
ea
rr
ho
Di
a
Vo
m
iti
n
se
a
a
pe
ci
Al
o
a
pe
ni
uk
o
Le
St
om
at
it
is
0
g
*
Na
u
*p<0,001
*
*
Women
Men
N = 1,093 f + 1,355 m patients receiving 5-FUbased chemotherapy
Sloan et al, J Clin Oncol 2002
Sex-based differences in
pharmacokinetics
• Sex-based differences in
pharmacokinetics have been
demonstrated
• Influence of sex (hormones ?) on
metabolism does exist for several
pathways and enzymes
• Clinical relevance: in most cases
slight over-/underdosing?
(Time (median, min)
Women emerge from general
anesthesia faster than men
10
9
8
7
6
5
4
3
2
1
0
Women
Men
time to eye opening
response to verbal
command
N = 274 patients receiving
propofol/alfentanil/NO
Gan TJ et al, Anaesthesiology 1999
CNS: GABA-receptors and sex/gender
• complex interaction between GABAA
receptors and sex hormones
• antinociceptive effects of progesterone via
binding at the GABAA-receptor complex
• chronic administration of progesterone
decreases the requirement of the narcotic
halothane in rats 
• pregnant women require smaller minimal
alveolar concentrations of volatile narcotics
when compared with non-pregnant women
Review: Pley et al, Acta Anaesthesiol Scand 2003
Influence of oral contraceptives (OC) on
the effect of benzodiazepines
35
Alprazolam
Lorazepam
30
Reaction index
25
20
with OC
without OC
15
10
5
0
AIM
DSST
AIM
DSST
Kroboth & McAuley, 1997
Sex / gender and requirements
of opiates
• In patient-controlled analgesia men require approx.
40 % higher doses of morphine than women (n = 1,833
patients).
• In healthy volunteers (n = 20; 10 females) using
electrostimulation to induce pain, the morphine concentration to decrease pain by 50 % came to 42 nmol/l
in women and 71 nmol/l in men.
• The required morphine concentration at the opiate
receptor for pain control is about twice as high in men
when compared with women.
• Women suffer more frequently than men from opiateinduced nausea and vomiting.
Review: Pley et al, Acta Anaesthesiol Scand 2003
Gender differences in treatment response to
sertraline vs. imipramine in chronic depression
70
P = 0.001 significant
interaction for
treatment*gender
women
men
60
50
40
30
20
10
0
imipramine
sertraline
n = 400 women
n = 235 men
Kornstein et al, Am J Psychiatry 2000
Sex/gender-differences in the
pharmacodynamis and effects of drugs
• Response to drugs can be sex-specific
• Differences can be observed even for those
receptors and enzymes for which a sexspecific response is not expected!
• Clinical relevance??
• Relevant for gender differences in drug
efficacy and incidence of side effects?
Age and sex distribution of suspected adverse drug
reactions to newly marketed drugs in general practice
in England: analysis of 48 cohort studies.
Martin RM et al, BJCP 1998
Gender-related differences in
pharmacokinetics and pharmacodynamics
• Sex/gender-based differences in drug
pharmacokinetics and effects do exist
• These differences are often small – but
become apparent in larger cohorts
• Thus: during drug development sexdifferences should be regarded –
and especially after drug approval!
Thank you for
your attention!
Analysis of trials with known gender-sensitive
drugs ??
Trials with substances, for which sex-differences were
known
Substance
Phase
% female
Gender analysis
Halofantrine
Phase I
14
No
Sotalol
Phase I
48
no
Erythromycin
Phase I
0
no
Desipramine
Phase I
58
no
Cisapride + Simvastatin
Phase I
0
no
Dihydroartemisinine
Phase I
?
no
Artesunate + Artemisinine
Phase I
0
no
Artesunate + Artemethere
Phase I
50
no
Tafenoquine
Phase I
0
no
Quinine
Phase I
0
no
QT-prolonging drugs
Antimalariamittel
Fleisch, Fleisch & Thürmann, CP&T 2005
Why do women live longer?
Geschlechtsspezifische Unterschiede in der
Pharmakokinetik von Psychopharmaka
• CYP 1A2: geringere Aktivität bei Frauen als bei
Männern. Dies führt zu etwa 35 % höheren
Plasmakonzentrationen von Clozapin und
Norclozapin bei Frauen im Vergleich zu
Männern.
• Die Plasmakonzentrationen der SSRIs
Fluvoxamin und Sertralin sind bei Frauen 70 –
100 % bzw. 50 – 70 % höher im Vergleich zu
Männern, dies wird auf unterschiedliche
Aktivitäten von CYP 1A2 und im Fall von
Fluvoxamin auch auf CYP 2C19 zurückgeführt.
Lane H-Y et al. J Clin Psych 1999; Meibohm B et al, Clin Pharmacokinet 2002
Drug development phases
Phase I: absorption, distribution, metabolism,
elimination, concentration/effect relationship,
healthy volunteers
Phase II: dose finding in selected patients,
comparison versus placebo (approx. 200)
Phase III: more patients (approx. 2,000), with
concomitant diseases and comedication,
comparison versus standard treatment
Phase IV: safetey after marketing aproval,
experience in a broad spectrum of patients
Hormonal Influences and efficacy of
antidepressants (I)
Martenyi et al, Eur Neuropsychopharmacol 2001
Hormonal Influences and efficacy of
antidepressants (II)
Martenyi et al, Eur Neuropsychopharmacol 2001
Age- and gender distribution of
digitalis intoxications
60
50
Men
Women
40
30
20
10
0
61-70
71-80
81-90
91-100
N = 123
Thürmann et al, Int J Clin Pharmacol Ther 2003
Dry cough induced by ACE-inhibitors
%
7
6
5
Men
Women
4
3
2
1
0
Enalapril
Lisinopril
Ramipril
Perindopril
16 non CV
drugs
Kubota et al, Eur J Clin Pharmacol 1996
Drug-induced QTc-prolongation in the
isolated rabbit heart
25
*
% deltaQT
20
*
female
male
15
10
5
0
d-Sotalol 10M
quinidine 3,3 M
*p < 0,05
Ebert SN et al, 1998